Protein-protein interactions form the bedrock of molecular biology, regulating such vitally important biological processes as cell proliferation, differentiation and death. Enormous research effort in the past several decades has revealed two dominant descriptions of protein- protein interactions: the "lock-and-key" and the "induced fit" paradigms. In the "lock-and-key" description, proteins are imagined as rigid bodies which perfectly fit into each other upon binding, while in the "induced fit" mechanism a conformational equilibrium between the native state and an excited state is shifted toward the latter due to preferential binding of some ligand. An alternative type of protein-protein interactions has been recognized in the last decade or so, that is in particular prevalent in the signal transduction, transcriptional and translational activities in eucaryotic cells. Either or both partner proteins in such interactions are partially or completely unfolded, necessitating intimate coupling of folding and binding. The aim of our proposed research is to use the powerful formalism of the energy landscape theory of protein folding to develop new analytical and computational models describing these interactions. We intend to apply the developed computational algorithms to investigate the mechanisms of coupled binding and folding in four specific protein-protein interaction systems implicated in human cancer development and in AIDS progression.